Miliary coccidioidomycosis mimicking tuberculosis: Case report and review of literature

Miliary coccidioidomycosis is a severe manifestation of diseases caused by Coccidioides immitis and Coccidioides posadasii that is endemic to the southwestern United States as well as Central and South America. While most cases of coccidioidomycosis present with pulmonary disease, certain risk factors increase the risk for disseminated disease. We present a case of miliary coccidioidomycosis in a 46-year-old patient with uncontrolled diabetes. Additionally, we review the features of thirty-seven cases of patients with miliary coccidioidomycosis.


Introduction
Coccidioidomycosis is a disease caused by the dimorphic fungi Coccidioides immitis and Coccidioides posadasii that is endemic to the southwestern United States, Washington State, as well as Central and South America [1,2].Initial infection occurs predominantly by inhalation of aerosolized arthroconidia and rarely by direct cutaneous inoculation [3,4].The main risk factor for its infection is living, working, or traveling in an area where Coccidioides is endemic [5].Immunocompromised persons, especially those with T-lymphocyte impairment or human immunodeficiency virus (HIV) infection, pregnant women (particularly in their third trimesters and immediately postpartum), and individuals with diabetes mellitus are at the highest risk of infection [6,7].The disease can be divided into three general categories: primary pulmonary infection (most common), extrapulmonary dissemination, and rarely, primary cutaneous coccidioidomycosis [8].
Disseminated coccidioidomycosis is rare but can manifest as a miliary pattern with chest imaging.Primary pulmonary and disseminated disease presents with symptoms similar to other respiratory illnesses; therefore, it is important to have a high index of suspicion for patients living or with recent travel to areas where Coccidiodes is endemic [9,10].
Here we present a case of miliary coccidioidomycosis, with an initial presentation mimicking miliary tuberculosis, which was diagnosed through positive IgM and IgG serologies.Furthermore, we describe the literature on miliary coccidioidomycosis in both immunocompromised and immunocompetent individuals.

Case presentation
A 46-year-old Hispanic female with a reported history of treated latent tuberculosis infection (LTBI), childhood polio, uncontrolled diabetes mellitus (A1c 12.9 %), androgen insensitivity syndrome (genotype XY, underwent bilateral orchiectomy in 2011 complicated by incidental seminoma), presented with 3 weeks of dry cough, shortness of breath, unintentional 25-pound weight loss, and headache (day 0).The patient stated that her symptoms started after driving through the "California Valley".On presentation (day 21), she was afebrile with a heart rate of 98, tachypneic to a respiratory rate of 28 with an oxygen saturation of 86 % on room air.Physical exam on admission was notable for diaphoresis and unremarkable lung exam.
Initial laboratory results were significant for normocytic anemia without leukocytosis (Hgb 11.4 g/dL) with chemistry showing hyponatremia (Na 126 mmol/L), non-anion gap respiratory alkalosis (pH 7.48, CO2 37 mmol/L), and elevated lactate (3.2 mmol/L).Further evaluation of the patient's persistent hyponatremia revealed a high urine osmolality (427 mOsm/kg) and urine sodium of 108 mmol/L.Initial chest radiograph was notable for a miliary pattern in the lungs, with airspace disease in the left upper lung zone (Figure A).A follow-up computed tomography (CT) (Figure B) scan of her thorax without contrast demonstrated diffuse bronchocentric-prominent nodularity, left upper lobe fibro-cavitary disease, and a few calcified granulomas.Given her recent travel history, Coccidioides serology studies (IgM and IgG), complement fixation, and identification were sent and were positive (IgM 0.774, IgG 1.811, complement fixation 1:16).
Acid-fast bacilli sputum cultures were unremarkable (day 24), and a QuantiFERON tuberculosis test was negative.Initial blood and sputum (fungal included) cultures did not show any pathogens and urine cultures demonstrated 35,000 CFU/mL Streptococcus agalactiae.
The patient was started on fluconazole 600 mg daily and salt tablets for the suspected syndrome of inappropriate diuretic hormone secretion (SIADH) secondary to pulmonary disease (day 25).Studies were negative for tuberculosis (described above), and legionella and histoplasmosis screening (urine antigen) was also negative.Risk of Sarcoidosis was low, so no specialized testing was obtained based on radiographic findings.She remained hospitalized for persistent hypoxia secondary to pulmonary disease and treatment of hyponatremia up until her discharge 11 days later after significant clinical improvement (day 32).On outpatient follow-up a month later (day 62), the patient was doing well and adherent to her fluconazole treatment, and detailed plans were made to repeat bloodwork, re-check Coccidioides titers, and obtain a CT chest to check for a clinical resolution.Unfortunately, she was lost to follow up shortly after that.

Discussion
Coccidioidomycosis is a relatively common infection.During 2000-2018, a total of 65,438 coccidioidomycosis cases were reported in California, with a median age-adjusted annual incidence of 7.9 per 100,000 population [11].Exposure to Coccidioides generally results in asymptomatic infection [12].Disseminated coccidioidomycosis, when the fungus spreads from the lungs, can present with a broad spectrum of clinical manifestations, but the fungus likes to infect the bones (especially the spine), joints, skin, meninges, and lymph nodes involving the neck.Immunosuppressed individuals living in endemic areas are at increased risk of disseminated disease [13,14].
The patient described in our case had uncontrolled diabetes as the main risk factor for disseminated disease.In our review of the literature, the most common comorbidities associated with miliary disease were diabetes (18 %), immunosuppression (33 %), and pregnancy (12 %) (Tables 1 and 2).The category of "immunosuppression," consisted primarily of HIV/AIDS, malignancy, transplantation, and use of immunosuppressive medications, factors which involved deficits in cellmediated immunity.There was also a predominance of males (79 %).Most of the miliary patterns seen on imaging were not accompanied by other radiological findings such as cavitation or consolidation, reflecting that this disseminated finding is not from a bronchopulmonary etiology or spread, but rather from the bloodstream seeding the pulmonary capillary beds [15].It is of interest that our case had both miliary nodularity as well as a left upper lobe cavitary lesion.Among the cases reviewed, most of the patients that were treated with an anti-fungal received amphotericin B (89 %), likely because of severe disease and/or because oral azoles were not available at the time, as 58 % of cases were reported before the year 2000.However, fluconazole was also used commonly (33 %) in those treated, either as monotherapy or in conjunction with amphotericin.Thirty percent (8/27) of patients received steroids as adjunctive therapy to the anti-fungal, of which 38 % (3/8) of these had clinical improvement and 62 % (5/8) died.It is difficult to ascertain the role and/or value of steroids, which were given to decrease the inflammation but could potentially cause further immunosuppression, from these case reports.It is also likely that the more severe cases received steroids, which may lead to higher mortality being reported in the literature.However, it is notable that those who did not get anti-fungal treatment and the 3 patients who received steroids only, all died, underscoring the life-threatening severity of miliary coccidioidomycosis.
The approach of diagnosis does not differ depending on the primary or disseminated disease.The gold standard continues to be a high degree of suspicion based on anamnesis and serological identification through antibody testing, and/or identification of Coccidioides spp in culture mediums and/or demonstrating the characteristic spherules on histology in biopsy specimens.
A miliary pattern on chest imaging is not specific for a disease or   pathogen and may be seen in metastatic cancer as well as several infectious organisms, including Mycobacterium tuberculosis and other fungi, most commonly from Coccidioides and Histoplasma [16].The miliary pattern reflects the seeding of the pulmonary capillary beds by some matter, most often cancer cells or infectious organism with such propensities, such as mycobacteria and fungi.The type and duration of antifungal treatment have not been standardized.Historically, treatment for primary coccidioidomycosis was only observation before the arrival of oral azoles.Nowadays, treatment is usually administered to patients who have more severe disease, require admission to the hospital, and/or those with risk factors for severe disease or dissemination, including diabetes mellitus, immunosuppression, pregnancy, and extreme ends of age [17].Studies have shown that while amphotericin B was found to be efficacious for the treatment of coccidioidomycosis, its adverse effects, including kidney injury, electrolyte (potassium and magnesium) depletion, and infusion-related reactions, were considered too great for routine use, except for the more severe infections [18][19][20].The azole anti-fungal class, which are significantly better tolerated and has a bio-available oral option for home use (such as for our patient), have been increasingly used in the more modern era.Our patient received fluconazole monotherapy and had a robust clinical response during her hospitalization and on initial follow-up.

Figure A .
Figure A. Miliary pattern in the lungs with airspace disease in the left upper lung zone.

Table 1
Reported cases of miliary coccidioidomycosis in adults.